French patent application no. 03/08660 previously described a method for forming a type of calcium phosphate hydroxyapatite, namely a product in granular form having good flow and compressibility properties. Hydroxyapatite is a natural mineral structure, often associated with bones and teeth, with a particular crystal lattice. As used herein, the term “hydroxyapatite” refers essentially to calcium phosphates that produce an X-ray diffraction pattern characteristic of hydroxyapatite. Hydroxyapatite is often designated in the trade by the term “tricalcic phosphate.” The ideal chemical formula of hydroxyapatite is Ca5(PO4)3(OH). It is, however, well known in the literature that the hydroxyapatite crystal lattice is extremely tolerant of anion and cation substitutions in the crystal network.
For example, the substitution of cations with elements such as magnesium, strontium, barium, sodium, lead and a large number of other atoms is well known. Anion substitution can take three different forms. First, a portion of the trivalent phosphate groups (PO43−) can be replaced by HPO42−. This results in a nonstoichiometric apatite structure. Second, the trivalent phosphate groups (PO43−) can be replaced by other complex anions such as carbonates or vanadates. Third, the hydroxyl group (OH) can be partially or completely replaced by other anions such as fluoride or chloride.
Coupled substitution, in which an ion is replaced by another ion with a different charge and in which the neutrality of the charge is maintained by substitutions elsewhere in the crystal lattice with ions of different charges or by vacancies in the crystal lattice, is also well known. In all of these substitutions, the factor that remains common, and distinguishes the material as being a hydroxyapatite, is its characteristic X-ray diffraction pattern.
French patent application no. 03/08660 describes a method for producing hydroxyapatite calcium phosphate granules having compressibility properties that are superior to other calcium phosphates. The calcium phosphate granules described therein also have a physical form that allows them to resist attrition, which retain significant internal porosity, and as a result dissolve rapidly when used. The structure of the calcium phosphate hydroxyapatite composition is obtained by a particular manufacturing method described in French patent application no. 03/08660.
The method for preparing the aforesaid hydroxyapatite calcium phosphate in granular form described in French patent application no. 03/08660 is characterized in that it involves processing a brushite dicalcium phosphate solution having a particle size such that 90% of the brushite particles are smaller than 260 microns and 90% of the particles are larger than 10 microns, using a basic solution, keeping the pH at no less than 7.0 for a sufficient period of time to allow the transformation of the brushite calcium phosphate into hydroxyapatite calcium phosphate. The method converts the brushite according to the following general equation for alkaline hydrolysis of brushite into hydroxyapatite:5 CaHPO4,2H2O+4 MOH+H2O→Ca5(PO4)3(OH)+2 M2HPO4+14 H2O  Equation [1]in which M is the cation contributed by the base, preferably an alkaline cation, for example Na+, K+ or NH4+. The pH is kept at a value of not less than 7.0, preferably between 7 and 10 and more preferably between 8 and 8.5.
The method described in French patent application no. 03/08660 involves a hydroxide base. The use of the bases NaOH, NH4OH, Ca(OH)2 and KOH is recommended. The method produces a hydroxyapatite in granular form that can be represented by the following formula:Ca5-x(PO4)3-x(HPO4)x(OH)1-x  (i)in which x varies between 0 and 1, and preferably between 0.1 and 0.5. As described in French patent application no. 03/08660, low quantities, for example less than 5% by weight, and preferably between 0.1 and 3% by weight, of calcium may be substituted with another cation, particularly the cation of the base (sodium, potassium). In addition, low quantities of trivalent phosphate groups (PO43−) may be substituted with complex anions (for example carbonate and vanadate) and hydroxyl ions replaced with another anion, for example a halide, particularly chloride or fluoride.
As shown by Equation [1], along with the hydroxyapatite, large quantities of an alkali metal phosphate, M2HPO4, are produced in the reaction. Among the disadvantages of the method described in French patent application no. 03/08660 is that the alkali metal phosphate is difficult to recycle or upgrade. Also, depending upon the particular base used, undesirable impurities may be present in the calcium phosphate hydroxyapatite.
The present inventors have discovered a method to prepare calcium phosphate hydroxyapatite granules that have an X-ray diffraction pattern characteristic of the mineral hydroxyapatite that are completely suitable for use as an excipient and that avoid the disadvantages of the prior methods described above.